The main focus of this project is to study the regulation and roles of atopic cytokines in the context of autoimmune and autoinflammatory diseases. We seek to do this by studying patients with syndromic atopy and autoimmunity/autoinflammation, utilizing mouse models of atopic and autoimmune disease, and investigating the basic mechanisms by which these cytokines are regulated and act on their target cells. Goal 1: We continue to enroll a cohort of patients with autoinflammatory disease (AD) and syndromic atopic features (AF). We now have a cohort of over 50 patients who exhibit features associated with severe atopy as well as syndromic autoimmunity and/or autoinflammation. This is a new project, and the main focus over the past year has been to accrue patients and perform clinical and immunophenotypic analysis. Preliminary immunophenotyping results reveal expansions of atopy-associated T helper subsets in these patients. Goal 2: We seek to understand the basic mechanisms through which atopic cytokines, including IL-9, are regulated. In collaboration with John OShea in the Molecular Immunology and Inflammation Branch, we have used mouse models of T helper differentiation to define a set of genes that are highly expressed in IL-9-producing T cells, or Th9 cells. We also identified two enhancers, or regions of noncoding regulatory DNA, that are critical for inducing expression of the Il9 gene. We determined that the vitamin A metabolite retinoic acid (RA) suppresses genes associated with Th9 cells through its receptor RA receptor (RAR) alpha. RA-RAR alpha also reduced accessibility of the two critical Il9 enhancers and blocked the actions of the activating transcription factors STAT5 and STAT6. We extended the significance of these findings to human disease by showing that tissue samples from patients with allergic disease showed higher expression of genes that RA suppresses in Th9 cells. These results were published in Immunity.